Parkinson's disease (PD) is a debilitating disorder that results from the progressive loss of dopaminergic (DAergic) nigrostriatal neurons. Underlying causes of this neurodegeneration are not known. Our current studies focus on understanding the relationship between adenosine and glutamate in mediating DAergic neurodegeneration, particularly under conditions of a metabolic stress as may occur in PD patients with defective mitochondria. In preliminary studies, the imposition of a metabolic stress in the striatum (via an infusion of malonate which blocks complex II of the electron transport chain) elevated extracellular glutamate levels in the substantia nigra (SN). Furthermore, blockade of glutamate N-methyl-D-aspartate (NMDA) or adenosine A2a receptors in the SN, but not the striatum, protected DAergic neurons against the mitochondrial stress. Based on these findings, we hypothesize that a striatal metabolic stress causes glutamate release in the SN and that A2a antagonists or metabotrobic glutamate group 2/3 agonists protect against stress-induced neuronal degeneration by inhibiting presynaptic glutamate release in the substantial nigra. This hypothesis will be tested in rats using intrastriatal infusion of a mitochondrial inhibitor in conjunction with the administration of either glutamatergic- or adenosinergic-acting agents. The ability of these interventions to protect DAergic neurons against a striatal metabolic stress will be examined by neurochemical measures in the striatum (content of tyrosine hydroxylase, dopamine and metabolites) and immunohistochemistry in the substantia nigra (stereological cell counts of TH+ and TH-/Nissl+ neurons (Aims #2,3,4). The ability of these interventions to modify glutamate release in the SN will be assessed using microdialysis techniques (Aims #1,2,3). In other studies, the subthalamic nucleus will be lesioned to determine if projections from this brain region to the SN are the source of the elevated glutamate and if A2a receptors are located on these STN-nigral projections (Aims #4,5). [unreadable] [unreadable]